Comparison of a novel salbutamol multidose powder inhaler with a salbutamol metered dose inhaler in patients with asthma

Comparison of a novel salbutamol multidose powder inhaler with a salbutamol metered dose inhaler in patients with asthma

CURRENT THERAPEUTIC RESEARCH® VOL. 58, NO. 10, OCTOBER 1997 COMPARISON OF A NOVEL SALBUTAMOL MULTIDOSE POWDER INHALER WITH A SALBUTAMOL METERED DOSE ...

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CURRENT THERAPEUTIC RESEARCH® VOL. 58, NO. 10, OCTOBER 1997

COMPARISON OF A NOVEL SALBUTAMOL MULTIDOSE POWDER INHALER WITH A SALBUTAMOL METERED DOSE INHALER IN PATIENTS WITH ASTHMA RITVA TAMMIVAARA,1 ERKKI AALTO, 2 KAARINA LEHTONEN, 3 VESA VILKKA, 4 KARI LAURIKAINEN,s MATTI SILVASTI,5 PETRI TOIVANEN,6 AND HANNU TUKIAINEN7

1Department of Pulmonary Diseases, Turku University Hospital, Turku, 2Department of Pulmonary Diseases, H~rm~i Hospital, H~irm~i, ~Kuusankoski Hospital, Kuusankoski, 4Department of Pulmonary Diseases, Etel~i-Karjala Central Hospital, Lappeenranta, 5Clinical Research, Orion Pharma, Kuopio, 6Unit of Biostatistics and Data Management, Orion Pharma, Espoo, and 7Department of Pulmonary Diseases, University of Kuopio, Finland

ABSTRACT On e h u n d r e d f i f t e e n a d u l t p a t i e n t s w i t h a s t h m a p a r t i c i p a t e d in t h i s o p e n - l a b e l , r a n d o m i z e d , p a r a l l e l - g r o u p s t u d y t h a t c o m p a r e d t h e acc e p t a b i l i t y , clinical efficacy, a n d t o l e r a b i l i t y o f s a l b u t a m o l i n h al at i o n a e r o s o l a n d p o w d e r in t h e t r e a t m e n t o f a s t h m a . T h e r e w e r e n o s i g n i f i c a n t d i f f e r e n c e s b e t w e e n g r o u p s in t e r m s o f d e m o g r a p h i c variables. Before the study the patients had used inhaled steroids at l e a s t f o r 6 m o n t h s a n d h a d s h o w n a n i m p r o v e m e n t in f o r c e d e x p i r a t o r y v o l u m e in 1 s e c o n d ( F E V I ) o r in p e a k e x p i r a t o r y f l o w r a t e ( P E F R ) o f m o r e t h a n 15% a f t e r t h e i n h a l a t i o n o f 200 pg o f s a l b u t a mol. T h e t r e a t m e n t p e r i o d w a s 12 w e e k s a n d w a s p r e c e d e d by a 2 - w e e k r u n - i n p e r i o d . T h e m e d i c a t i o n s w e r e d e l i v e r e d f r o m a m etered dose inhaler (MDI) and from a new multidose powder inhaler ( M D P I ) . D u r i n g t h e study, h o m e P E F R w a s m e a s u r e d d ai l y i n t h e m o r n i n g s a n d in t h e e v e n i n g s . I n t h e m o r n i n g s P E F R w a s m e a s u r e d b o t h b e f o r e a n d 15 m i n u t e s a f t e r t h e i n h a l a t i o n o f 200 pg o f salbutamol. FEV 1 and forced vital capacity (FVC) w e r e measured after t h e r u n - i n p e r i o d a n d a f t e r 4 a n d 12 w e e k s o f t r e a t m e n t . FEV, a n d FVC w e r e m e a s u r e d i m m e d i a t e l y b e f o r e a n d 15 a n d 30 m i n u t e s a f t e r t h e i n h a l a t i o n o f 200 pg o f s a l b u t a m o l . A s t h m a s y m p t o m s c o r e s , adverse events, and the use of rescue medication were recorded daily. P a t i e n t s ' p r e f e r e n c e o f t h e i n h a l e r s ( a c c e p t a b i l i t y ) w a s e v a l u a t e d d u r i n g t h e s t u d y a f t e r 4 w e e k s o f t r e a t m e n t . No s i g n i f i c a n t d i f f e r e n c e s w e r e f o u n d b e t w e e n t h e t r e a t m e n t s in a n y o f t h e efficacy v a r i a b l e s m e a s u r e d . O f t h e 77 p a t i e n t s a l l o c a t e d t o u s e t h e n e w MDPI, 72 g a v e t h e i r o p i n i o n a b o u t t h e i n h a l e r s : 34 p a t i e n t s (47%) r a t e d MDPI e a s i e r t o u s e t h a n t h e MDI; 28 ( 3 9 % ) did n o t f i n d a n y d i f f e r e n c e s i n h a n d l i n g b e t w e e n t h e t w o d e v i c e s ; a n d 10 ( 1 4 % ) f e l t t h e MDPI w a s m o r e d i f f i c u l t t o u s e t h a n t h e MDI. We c o n c l u d e t h a t

Address correspondence to: Kari Laurikainen, Lic. Odont., Clinical Research, Orion Pharma, P.O. Box 1780, Fin-70701 Kuopio, Finland. Receivedfor publication on June 24, 1997. Printed in the U.S.A. Reproduction in whole or part is not permitted. 734

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R. TAMMIVAARA ET AL.

the n e w MDPI is clinically equivalent t o the MDI in the long-term t r e a t m e n t o f asthma, and the patients found it easy to use. K e y words: aerosol, asthma, dry powder inhaler, salbutamol. INTRODUCTION

Thinning--and even holes--have been found in the ozone layer, especially around both polar regions. Studies 1'2 indicate that fluorocarbons currently used in the metered dose inhalers (MDIs) are contributing to the destruction of the ozone layer that is so important to our well-being. Although the amount of fluorocarbons used in drug delivery systems is small compared with the total consumption of fluorocarbons, the international restrictions 3'4 on the use of fluorocarbons has been extended to include their use in medical devices. The administration of pressurized drugs has also been shown to be far from optimal in many patients. Problems in the timing of the actuation of the MDI to the inhalation (hand-lung coordination), local irritation of the throat causing cough or hoarseness, and allergy to fluorocarbons, surfactants, or lubricants m a y lead to ineffective therapy. ~ To avoid these major problems of MDIs and to improve the inhalation therapy, a multidose powder inhaler (MDPI) without propellants and surfactants has been developed. The new MDPI, Buventol Easyhaler (Orion Pharma, Espoo, Finland), resembles the MDI in outer design and handling. It has also a similar dose-releasing system as the MDI. The new MDPI is an unpressurized, inspiratory-flow-driven device that contains 200 drug doses and enables drug inhalation without the need for handlung coordination. In previous single-dose clinical studies, 6'7 the new MDPI was as effective as the MDI in delivering equal doses of salbutamol to patients with asthma. This study compared the acceptability, clinical efficacy, and tolerability of a conventional salbutamol MDI and the novel salbutamol MDPI in patients with mild to moderately severe a s t h m a treated with inhaled steroids. PATIENTS AND METHODS

Patients

One hundred fifteen patients (70 women, 45 men) entered the study. Patients were eligible if they were older than 18 years of age, had used inhaled steroids at least for 6 months before the study, and had shown an improvement in forced expiratory volume in 1 second (FEV1) or in peak expiratory flow rate (PEFR) of more than 15% after the inhalation of 200 ~Lgof salbutamol as shown within 6 months before the study. The exclusion criteria were hypersensitivity to sympathomimetics or any other compo735

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nent of the study preparations, significant cardiac disease, inadequately controlled hyperthyroidism, use of beta-blockers, or insulin-dependent diabetes. Pregnant women were also excluded. Data from two patients who discontinued the study in the beginning of the run-in period were not recorded in the database. Thus the database contains data from 113 patients who were randomly assigned to receive MDPI (n = 77) or MDI (n = 36). Before the study all patients used inhaled steroids and inhaled sympathomimetics. In addition, 16 patients (9 in the MDPI group and 7 in the MDI group) used theophylline. In the MDPI group two patients used nedocromil medication and one used sodium cromoglycate in addition to inhaled steroids and inhaled sympathomimetics. Before the control visits the patients abstained from bronchodilating drugs as follows: from controlledrelease theophyllines for at least 48 hours, from oral sympathomimetics at least 12 hours, and from all other inhaled drugs (except inhaled steroids) 8 hours. Long-acting inhaled beta2-sympathomimetics were not allowed during the study. Before enrolling, all patients were given oral and written information concerning the study, and written informed consent was obtained. The study was carried out according to the Declaration of Helsinki and was approved by local ethics committees.

Study Design The trial was an open-label, randomized, parallel-group study carried out in 13 centers in Finland. It consisted of a run-in period of 2 weeks followed by a treatment period of 12 weeks. Patients visited the study sites four times. At the first visit the patients were screened, and their eligibility was checked. This visit was followed by a 2-week run-in period during which the patients started the regular use of salbutamol (MDI 100 ~g/dose, two puffs twice daily [BID]). During the run-in period the patients measured P E F R twice daily with a Spira Peak Flow Meter (Respiratory Care Center, H~imeenlinna, Finland) and recorded asthma symptoms, the use of rescue medication, and the occurrence of adverse events daily. In the morning P E F R was measured both before and 15 minutes after the inhalation of study drugs and in the evening before any drug inhalations. At each measurement three readings were taken and entered in the diary. The highest value was used in the analysis. Severity of a s t h m a symptoms during the day and at night was recorded using a 10-point rating scale (0 = no symptoms, 1 to 3 = mild symptoms, 4 to 6 = moderate symptoms, and 7 to 9 = severe symptoms). During the second visit (immediately after the run-in period), FEV1 and forced vital capacity (FVC) were measured three times: immediately 736

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before (baseline) and 15 and 30 minutes after the inhalation of 200 ttg of salbutamol from the MDI. The t r e a t m e n t period started after the second visit. The test t r e a t m e n t was a salbutamol inhalation powder delivered from the new MDPI. The dosage of the MDPI was one inhalation BID. The control medication was a salbutamol inhalation aerosol delivered from an MDI (Ventolin ® 100 ~g/ dose, Glaxo Wellcome, Uxbridge, United Kingdom), and the dosage was two puffs BID. During the study the patients were allowed to use inhaled salbutamol as a rescue medication. Those who were allocated to the MDPI group h a d a salbutamol MDPI (Buventol Easyhaler 100 ~g/dose) as a rescue medication, and those in the MDI group had a salbutamol MDI (Ventolin ® 100 ~g/dose) as a rescue medication. No other sympathomimetics were allowed. Concomitant a s t h m a medication as well as the t r e a t m e n t of other possible diseases were kept the same as prescribed before the study. PEFR and the use of rescue medication were noted daily during the study. Asthma symptoms and adverse events were assessed daily during two different periods of 2 weeks each (weeks 3 and 4 and weeks 11 and 12 of the t r e a t m e n t period). Patients visited the study site after 4 and 12 weeks of t r e a t m e n t (3rd and 4th visits), and spirometry was performed at each visit. The patients in the MDPI group used their powder inhalers in the bronchodilatation test, whereas those in the MDI group used salbutamol inhalation aerosol. The patients' preference of the inhalers (acceptability) was assessed after 4 weeks of treatment. The patients in the MDPI group were asked to choose one of the following statements: 1 = MDPI is easier to use t h a n the MDI they had used during the run-in period, 2 = no differences between the devices in handling, and 3 = MDPI is more difficult to use t h a n the MDI.

Statistical A n a l y s i s Patients were randomly allocated to either t r e a t m e n t group; the allocation ratio of 2:1 was used so t h a t the number of patients in the MDPI group was twice t h a t in the MDI group. The study centers were randomized separately. The change in the morning PEFR was used as a primary efficacy variable. For the analysis of the PEFR values the morning measurements before inhalation were subtracted from the values after inhalation. The means of these changes were calculated from three 2-week periods: the two run-in weeks, t r e a t m e n t weeks 3 and 4, and t r e a t m e n t weeks 11 and 12. To be included in the calculation of the mean values of a particular period, patients had to provide d a t a at least from 7 days during each period. A change variable was set aside if either of the values (before or after inha737

SALBUTAMOL MULTIDOSE P O W D E R INHALER

lation) was missing. The estimate of the error variance was achieved from the analysis of variance model. For a s t h m a symptoms, cumulative sum scores were calculated from analogous 2-week periods. Scores were evaluated for symptoms during the day and night separately. The differences between the groups were tested with Wilcoxon's rank sum test. Responses for FEVx and FVC measurements were constructed by subtracting the value before inhalation from the value 30 minutes aider inhalation. A design of three successive measurements and treatment group was analyzed by fitting a repeated measures model for both variables. Contrasts for the differences between the treatments at every time point and 95% confidence intervals for these were also calculated. All statistical computations were performed with the SAS statistical package (Release 6.01, SAS Institute, Inc., Cary, North Carolina). A twosided P value of less than 5% was considered statistically significant. RESULTS

A total of 106 patients completed the study (71 in the MDPI group and 35 in the MDI group). Nine patients discontinued the study, 7 (6 in the MDPI group and i in the MDI group) during the run-in period and 2 (both in the MDPI group) during the t r e a t m e n t period because of serious adverse events (brain tumor and adenocarcinoma of the lungs). There was no causality between these events and the study medications. There were no significant differences between groups in terms of age, height, body weight, Table I. Summary of patient characteristics.

Sex (n) Male Female Age(y)* . Height (cm) Body weight (kg)* Duration of asthma (y) Daily dose of inhaled steroids (pg)* Beclomethasone Range Budesonide Range FEV1 at the beginning of the study* L % of predicted NO. of atopics

MDPI Group (n = 77)

MDI Group (n = 36)

31 46 49+13 167 ± 9 71 + 14 8.4 + 8.6

12 24 49+14 168 + 7 72 + 16 0.4 + 9.9

1041 + 324 400-2000 956 ± 316 400-1600

1100 + 373 500-2000 1033 _+413 400-1600

2.7 ± 0.9 82.5 ± 18.2 35

2.5 _+1.0 74.4 + 20.8 19

MDPI = multidose powder inhaler; MDI = metered dose inhaler; FEV1= forced expiratory volume in 1 second. * Mean + $D.

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~

30.

25.

"6 20. "~15. z 10. .

.

.

.

.

.

Easier

I

Equal

More Difficult

Not Known

Figure 1. Patients' preference of the inhalers (acceptability). The MDPI patients were asked to choose one of the following alternatives: The new multidose powder inhaler (MDPI) is easier to use t h a n the metered dose inhaler (MDI) (Easier); there is no difference between the devices (Equal); or MDPI is more difficult to use t h a n the MDI (More Difficult). Opinions of five patients are missing (Not Known).

duration of asthma, daily dose of inhaled steroids, FEV1 at the beginning of the study, or the number of atopics used. Patient characteristics are shown in Table I.

Acceptability of the Inhalers After 4 weeks of treatment, patients in the MDPI group were asked to compare the MDPI with the MDI they had used during the run-in period. Responses were obtained from 72 patients: 34 patients (47%) felt that the new MDPI was easier to use than the MDI; 28 patients (39%) did not find differences between the devices; and 10 patients (14%) found the MDPI more difficult to use than the MDI (Figure 1). For unknown reasons, five patients did not complete the diary properly and their answers were missing.

Efficacy During the run-in period there was a slight difference between the groups in the baseline mean morning and evening P E F R values with values being slightly higher in the MDPI group; these differences persisted throughout the study (Figures 2A and 2B), although they were not statis739

SALBUTAMOL MULTIDOSE POWDER INHALER

A.

[ ] Change

500

IIPre

450 400 350 ~E

300 250

u¢ 200 U.I 150 100 50 0

MDPI Run-in

MDI

MDPI

MDI

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MDI

Weeks 11-12

B.

450 I

400

350 C



MDPI

[]

MDI

3O0

~250 ,,m 200 LU O.

150 100 5O 0 Run-in

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Weeks 11-12

Figure 2. (A) The m e a n peak expiratory flow rate (PEFR) in the morning before the drug inhalation (Pre) a n d 15 minutes aider the inhalation of 200 ~g of salbutamol (Change). Salbutamol was inhaled e i t h e r from t h e multidose powder i n h a l e r (MDPI) or from the metered dose inhaler (MDI). During the run-in period all patients used MDI. (B) The m e a n PEFR in the evening before the drug inhalation.

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R. TAMMIVAARAETAL.

Table II. Values (mean ± SD) of forced expiratory volume in 1 second (FEVz), absolute values (L) before (baseline) and 15 and 30 minutes after the inhalation of 200 ~Lg of salbutamol.*

After the run-in period Baseline 15 Minutes postdose 30 Minutes postdose Change from baseline After 4 weeks' treatment Baseline 15 Minutes postdose 30 Minutes postdose Change from baseline After 12 weeks' treatment Baseline 15 Minutes postdose 30 Minutes postdose Change from baseline

MDPI Group

MDI Group

2.76 ± 0.90 3.01 ± 0.87 3.05 ± 0.88 0.29 ± 0.24

2.53 ± 0.97 2.78 ± 0.95 2.81 ± 0.95 0.28 ± 0.21

2.75 ± 0.88 2.93 ± 0.84 2.97 ± 0.83 0.22 ± 0.18

2.48 ± 0.98 2.71 ± 0.95 2.74 ± 0.93 0.26 ± 0.17

2.74 ± 0.89 2.94 ± 0.88 2.97 ± 0.85 0.23 ± 0.21

2.45 + 0.93 2.71 ± 0.93 2.75 ± 0.92 0.30 ± 0.20

MDPI = multidose powder inhaler; MDI = metered dose inhaler. * In the first bronchodilatation test (after the run-in period) all patients used an aerosol inhaler. In the second and third tests the MDPI group used a powder inhaler and the MDI group an aerosol inhaler.

tically significant. D u r i n g t h e r u n - i n period t h e i n c r e a s e s ( m e a n + SD) in t h e m o r n i n g P E F R v a l u e s aider t h e i n h a l a t i o n of s a l b u t a m o l w e r e 54 + 33 L / m i n in t h e M D P I g r o u p a n d 53 + 30 L / m i n in t h e M D I group. At t h e e n d of the s t u d y t h e m e a n i n c r e a s e s w e r e 48 + 26 L / m i n a n d 55 + 30 L/min, respectively.

Spirometry T h e r e w a s a s m a l l b u t n o t significant difference in t h e m e a n baseline FEV1 v a l u e s b e t w e e n t h e g r o u p s a f t e r the r u n - i n period (Table II). I n

Table III. Cumulative asthma symptom scores (mean ± SD).*

Asthma symptoms during the day Run-in Weeks 3-4 Weeks 11-12 Asthma symptoms at night Run-in Weeks 3-4 Weeks 11-12

MDPI Group

MDI Group

22.0 ± 19.1 23.4 ± 20.4 22.3 + 18.5

24.5 ± 23.4 25.4 ± 22.5 23.0 ± 19.7

10.1 + 14.4 11.9 ± 18.4 9.5 ± 13.7

13.3 ± 23.6 10.4 ± 17.6 11.0 + 15.1

MDPI = multidose powder inhaler; MDI = metered dose inhaler. * Severity o1asthma symptoms was recorded using a lO-point rating scale (0 = no symptoms, 1 to 3 = mild symptoms, 4 to 6 = moderate symptoms, and 7 to 9 = severe symptoms). A theoretical maximum of 126 (14 days x a high score of 9 each day) was possible.

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response to inhaled salbutamol, the FEV 1 values increased similarly in both groups in the first bronchodilatation test after the run-in period. The increase (mean + SD) in FEV1 30 minutes after the inhalation of salbutamol was 0.28 + 0.24 L in the MDPI group and 0.29 ± 0.21 L in the MDI group. At the end of the study the mean increases were 0.23 ± 0.21 L and 0.30 ± 0.20 L, respectively. The FVC values paralleled those of the FEV1, and the changes after the inhalation of salbutamol were similar in both groups. No statistically significant differences were found in FEV 1 or FVC between groups.

Asthma Symptoms A cumulative score was calculated separately for the run-in period, for weeks 3 and 4, and weeks 11 and 12 of the t r e a t m e n t period. The cumulative scores during the day ranged from 22.0 to 25.4; at night the cumulative scores ranged from 9.5 to 13.3. The theoretical m a x i m u m score was 126 (14 days x a m a x i m u m score of 9). No significant difference was found between the t r e a t m e n t groups (Table III).

Use o f Rescue Medication During the run-in period, use of salbutamol inhalations (mean + SD) was 8.1 + 13.9 puffs/wk in the MDPI group and 14.9 + 20.7 puffs/wk in the MDI group. During weeks 3 to 4 of the t r e a t m e n t period the respective use was 9.1 + 19.8 puffs/wk and 15.6 + 22.9 puffs/wk. The differences between the groups were not statistically significant. At the end of the study (weeks 11 to 12 of the t r e a t m e n t period) mean use of the rescue medication was 4.7 + 8.8 puffs/wk in the MDPI group and 10.8 + 19.1 puffs/wk in the MDI group.

Tolerability During the t r e a t m e n t period 40 patients reported adverse events, 29 patients (41%) in the MDPI group and 11 patients (31%) in the MDI group. The most commonly reported symptoms were respiratory infections and asthma-related symptoms such as chest tightness and shortness of breath. Five patients (7%) in the MDPI group and four (11%) in the MDI group complained of tremor or palpitations. DISCUSSION AND CONCLUSIONS

This is the first long-term acceptability and efficacy study of salbutamol inhalation powder administered from the new MDPI. Patients used in742

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E T AL.

haled salbutamol regularly either from the MDPI or from the conventional MDI for 12 weeks. The regular use of salbutamol was chosen to acquire information on reliable functioning of the new powder inhaler although the present guidelines for the t r e a t m e n t of asthma recommend the "as required" use of short-acting sympathomimetics, s Based on this study, both tested inhalers gave a similar bronchodilating effect in the long-term treatment of asthma, thus confirming equal clinical efficacy. This finding is in concordance with previous single-dose trials performed with Buventol Easyhaler. 6'7 The incidence of drug-related adverse events (tremor/palpitation) was low (probably due to the small doses used in the study), and there were no differences between the treatment groups. In this study the patients used regularly inhaled steroids (median, 1000-~g beclomethasone or 800-~g budesonide/d), and they were in good clinical condition when entering the trial. Thus the response to the inhaled salbutamol was only modest (between 8% and 10% increase in P E F R or FEV1), although during the past 6 months before the study they had shown more than a 15% increase in P E F R or FEV 1 after the inhalation of 200 ~Lg of salbutamol. Despite the randomization, there was a small difference in the baseline lung function values between the groups, and the difference persisted over the whole t r e a t m e n t period. The patients in the MDI group were more obstructive as reflected by the baseline lung function values. Before the trial, most patients were familiar with MDI devices and were instructed to use them correctly. However, aider 4 weeks of t r e a t m e n t almost half of the patients who had used Buventol Easyhaler rated it easier to use than the MDI, whereas one third found no difference between the devices. A similar trend existed already in previous single-dose trials, 6'7 b u t the difference was even more evident in this study. The new MDPI resembles the MDI in outer design and also partly in the method of drug administration. These similarities m a y facilitate the fluent shift from MDIs to MDPIs. According to the results of this study the new inspiratory-flow-driven salbutamol MDPI has the same bronchodilating effect and is as well accepted as the traditional salbutamol MDI in the t r e a t m e n t of asthma. In our study, the majority of the patients who used the MDPI found it easier to use than the conventional MDI.

Acknowledgments The study was sponsored by Orion Pharma, Kuopio, Finland. The authors t h a n k the following physicians who participated in the study: M a r k k u J~irvinen and Eero Mikkola, Kanta-H~ime Central Hospital; Tuomo Kava, Private Allergy Clinic; Sirkka Koskinen and Tuula Viljanen, 743

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Kiljava Hospital; Jukka Laitinen, Private Clinic of Tampere; Arvid Nyberg, Porvoo Hospital; Pekka Saarelainen, Laakso Hospital; Kari Alanko, P/iij~it-H~ne Central Hospital; Martti Torkko, Mikkeli Central Hospital; and Anne Laatikainen, Kuopio University Hospital, Finland. References: 1. Jeevan A, Kripke ML. Ozone depletion and the immune system. Lancet. 1993;342:11591160. 2. Lloyd AS. Stratospheric ozone depletion. Lancet. 1993;342:1156-1158. 3. Montreal Protocol 1987. Montreal protocol on substances that deplete the ozone layer. Montreal; 1987. 4. The Commission of the European Communities. Commission Decision of 26 July 1995 on the quantities of controlled substances allowed for essential uses in the Community in 1996 under Council Regulation (EC) No 3093/94 on substances that deplete the ozone layer (95/324/EC). Brussels: European Communities; 1995. 5. Grompton GK. Problems patients have using pressurized aerosol inhalers. Eur J Respir Dis. 1982;63:101-104. 6. Nieminen MM, Vidgren M, Laurikainen K, et al. Easyhaler, a novel multiple dose inhaler; clinically equivalent with salbutamol MDI and easier to use. Respiration. 1994; 61:37-41. 7. Vidgren M, Silvasti M, Korhonen P, et al. Clinical equivalence of a novel multiple dose powder inhaler versus a conventional metered dose inhaler on bronchodilating effects of salbutamol. Arzneimittelforschung. 1995;45:44-47. 8. British Thoracic Society. The British guidelines on asthma management---1995 review and position statement. Thorax. 1997;52(Suppl 1):S1-$21.

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